Copper-catalyzed, stereoconvergent,: Cis -diastereoselective borylative cyclization of ω -mesylate- α, β -unsaturated esters and ketones

Article abstract of DOI:10.1039/c7ob01382e

The Cu(i)-catalyzed stereoconvergent borylative cyclization of ω-mesylate-α,β-unsaturated compounds is facilitated by a simple Cu-bisphosphine catalyst. This reaction provides a novel route to cis-β-boron-substituted five- and six-membered carbocycle and heterocycle esters. Mechanistic studies indicate that stereoconvergence and cis-substitution likely stem from the rapid enolation of the borylcopper adduct with the substrate double bond and the formation of a five-membered intermediate, respectively.

Full text of DOI:10.1039/c7ob01382e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
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DOI: 10.1039/C7OB01382E
Journal Name
Copper-Catalyzed, Stereoconvergent, cis-Diastereoselective
Borylative Cyclization of ω-Mesylate-α,β-Unsaturated Esters and
Ketones
Received 00th January 20xx,
Accepted 00th January 20xx
a,†
b,†
b,†
b,c,
DOI: 10.1039/x0xx00000x
Ya-Jie Zuo, Xiao-Tong Chang, Zhi-Ming Hao, and Chong-Min Zhong
*
www.rsc.org/
The Cu(I)-catalyzed stereoconvergent borylative cyclization of ω-mesylate-α,β-unsaturated compounds is facilitated by a
simple Cu-bisphosphine catalyst. This reaction provides a novel route to cis-β-boron-substituted five- and six-membered
carbocycle and heterocycle esters. Mechanistic studies indicate that stereoconvergence and cis-substitution likely stem
from the rapid enolation of the borylcopper adduct with the substrate double bond and the formation of a five-membered
intermediate, respectively.
Five- and six-membered carbocycles are common motifs in bearing a terminal leaving group has not yet been reported. In
both natural and synthetic compounds that exhibit important this context, 2-alkoxycarbonylcycloalkyl boronate is a potential
biological and pharmaceutical activities. Cycloalkylboron synthetic intermediate for the preparation of cyclic β-amino
compounds are important building blocks for the acids, which have attracted the attention of synthetic and
10
stereoselective preparation of a wide range of carbocycles due medicinal chemists over the past two decades due to their
11
to their versatility for derivatization. In general, interesting bioactivities. As part of our studies into borylative
8
b, 12
cycloalkylboron compounds are prepared1 via the C–C bond formation,
we herein report the first copper-
hydroboration of cycloalkene derivatives, or the catalyzed stereoconvergent borylative cyclization of ω-
2
hydrogenation of cycloalkenylboronates. However, in recent mesylate-functionalized α,β-unsaturated esters and ketones to
years, the metal-catalyzed intramolecular borylative cyclization afford five- and six-membered cycloalkylboronates bearing
reaction has appeared as a novel method for the preparation either a 2-alkoxycarbonyl or 2-acyl substituent, with high levels
13
of boron-containing cyclic compounds. For example, Cárdenas of cis-selectivity (Scheme 1).
and Bäckval reported the Pd-catalyzed borylative cyclization of
3
4
1
,6-enynes and enallenes, respectively. However, Cu-
catalyzed borylative cyclization reactions have attracted more
attention, with Lam et al. reporting an enantioselective
copper-catalyzed domino conjugate boration/aldol cyclization
of enone diones to produce a range of highly functionalized
5
bicyclic compounds. In addition, Liu et al. achieved a tandem Scheme 1. Copper-Catalyzed Stereoconvergent Borylative Cyclization
regioselective β-borylation of an alkyne/conjugate addition
reaction of cyclohexadienone-containing 1,6-enynes, which
The borylative cyclization of model compound (Z)-ethyl 6-
[(methylsulfonyl)oxy]-2-hexenoate [(Z)-1a] was carried out
6
also yielded highly functionalized bicyclic compounds.
Furthermore, Ito et al. reported the Cu-catalyzed borylative using bis(pinacolato)diboron (2) in the presence of
exo-cyclization of alkenyl halides to produce monocyclic and CuCl/PCy
spirocyclic compounds. Ito’s works show that Cu-catalyzed yield. Analysis by H NMR spectroscopy and GC-MS confirmed
/KOtBu in THF at 25 °C (Table 1) to yield 3a in 84%
3
7
1
10
diastereoselective borylative cyclization of terminal- that 3a is a mixture of cis- and trans-3a (9:1). Thus, to
functionalized α,β-unsaturated aromatic and silyl compounds improve the stereoselectivity, several bisphosphine ligands
can be employed to synthesize cyclopropyl and were screened (Table 1, entries 2–7). As indicated in Table 1,
8
cyclobutylboronates. Although the hydroboration of α,β- 1,1ʹ-bis(diphenylphosphino)ferrocene (dppf, entry 2), (±)-2,2ʹ-
unsaturated esters, ketones, amides, aldehydes, thioesters, bis(diphenylphosphino)-1,1ʹ-binaphthyl (binap, entry 3), and
and nitriles9 is wildly used to prepare organoboron 1,4-bis(diphenylphosphino)butane (dppb, entry 4) did not yield
compounds, the borylative cyclization of such substrates any
improvement
in
stereoselectivity,
and
1,1-
bis(diphenylphosphino)methane (dppm) gave a poor yield
(entry 5, 26%). In addition, 1,3-bis(diphenylphosphino)propane
(dppp) afforded cis-3a in >99% selectivity but only 56% yield
(entry 6), while 1,2-bis(diphenylphosphino)ethane (dppe) gave
an improved yield of 67% with >99% cis-selectivity (entry 7).
Furthermore, the N-heterocyclic carbine (NHC) ligand IPr gave
a poorer yield and a lower selectivity (entry 8, 52% yield, 85%
cis-selectivity).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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ARTICLE
Journal Name
a
a
Table 1. Condition optimization for the copper-catalyzed borylative cyclization
Table 2. Scope and limitations
View Article Online
DOI: 10.1039/C7OB01382E
b
Entry
Reactant
Product
Yield (%)
1
40
44
70
Yield
c
Entry
Ligand/Equiv. Solvent
b
cis-3a/trans-3a
(%)
2
3
d
1
2
3
4
5
6
7
8
9
PCy /0.2
THF
THF
84
76
65
51
26
56
67
52
80
90:10
90:10
85:15
90:10
‒
3
dppf/0.1
(±)-binap/0.1 THF
dppb/0.1
dppm/0.1
dppp/0.1
dppe/0.1
THF
THF
THF
THF
>99:
>99:
<
<
1
1
4
40
IPr⋅HCl/0.1 THF
85:15
97:3
99:1
dppe/0.1
dppe/0.1
dppe/0.1
dppe/0.1
toluene
1
1
1
a
0
1
2
1,4-dioxane 89
DMF
DMF
95(86) 99:1
82 99:1
e
5
6
56
82
Conditions: 1a (0.5 mmol), 2 (0.6 mmol), CuCl (0.05 mmol), KOtBu (0.5 mmol),
solvent (1.0 mL), 25 °C, 16 h. GC yields. Isolated yields are shown in parenthesis.
Determined by H NMR spectroscopy. Cy = cyclohexyl. (E)-1a was used.
b
c
1
d
e
To further improve the yield, the reaction employing dppe
was attempted in a range of solvents (entries 9–11). Reaction
in toluene afforded 3a in 80% yield, but with a slight decrease
in selectivity (entry 9, 97%), while reaction in 1,4-dioxane gave
an improved yield of 89% with 99% cis-selectivity (entry 10).
An almost quantitative yield (and excellent cis-selectivity) was
obtained when the reaction was carried out in DMF (entry 11,
7
8
71
76
9
5%).
To investigate the stereochemical relationship between
substrate and product, the reaction was carried out using (E)-
instead of (Z)-1a under previously optimized conditions
Table 1, entry 11). Cis-3a was produced in a comparable
isolated yield and selectivity to the reaction using (Z)-1a
entries 11 and 12). These results indicate that
1
a
(
9
50
(
stereoconvergent transformation is crucial for obtaining
products exhibiting excellent cis-selectivity, as it is both
difficult and tedious to obtain pure E or Z alkenes.
A series of cycloalkyl boronates containing an electron
withdrawing group and a boron atom on the same side of the
ring were then synthesized using a CuCl/dppe catalyst in DMF
1
0
52
complex
mixture
(Table 2). In this case, the six-membered ring product cis-3b
1
1
1
1
2
3
was produced from both (E)-1b and (Z)-1b in half the isolated
yield of that obtained for the five-membered ring product
c
65
(entries 1 and 2). This low yield may be due to decomposition
during the isolation process. We then investigated the effect of
employing ester groups containing different alkyl substituents,
such as benzyl, para-methoxybenzyl, cinnamyl, and para-
chlorophenylethyl (Table 2, entries 3–6), and the
corresponding five-membered ring boronates were obtained
c
65
c
1
4
62
in moderate to good yields (cis-3c, 70%; cis-3d, 40%; cis-3e
6%, and cis-3f, 82%). Substrates (E)-1g and (E)-1h, which bear
a methyl group at the α-position of the acrylate, were also
,
5
a
Conditions: 1 (0.5 mmol), 2 (0.6 mmol), CuCl (0.05 mmol), dppe (0.05 mmol),
b
c
KOtBu (0.5 mmol), DMF (1.0 mL), 25 °C, 16 h. Isolated yield. NMR yields.
used to give the corresponding five- and six-membered ring
2
| J. Name., 2012, 00, 1-3
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
products cis-3g and cis-3h in moderate yields (entry 7, cis-3g
ARTICLE
,
the presence of CD OD under identical conditions. Indeed, 5:1
3
View Article Online
DOI: 10.1039/C7OB01382E
were obtained following the
7
1%; entry 8, cis-3h, 76%). In this case, the higher yield of cis- mixtures of syn-
5
and anti-
5
15
3
h
is attributed to the improved stability of its quaternary hydroboration reactions of both (E)-
4
and (Z)-
4
.
This result
carbon center. Furthermore, the introduction of a methyl indicates that a mechanistic study into the hydroboration of
group at the terminal of the chain [(E)-3i] produced a mixture (E)- and (Z)- should provide key information to aid in the
4
4
of cis-3i and trans-3i (entry 9, cis-3i/trans-3i = 56/44). In understanding of the stereoconvergent characteristics of these
addition to acrylates, α,β-unsaturated ketone (E)-1i reacted borylative cyclization reactions.
smoothly to produce cis-3i in moderate yield (entry 10, 52%).
Unfortunately, these reaction conditions are not applicable to was then measured for the hydroboration of (E)-
the synthesis of four-membered ring products (entry 11). and the results are shown in Table 3. To eliminate any
In addition to carbocycles, we found that oxygen- and influences arising from small differences in reaction conditions,
nitrogen-containing substrates (E)-1l, (Z)-1l and (E)-1m were a competitive reaction using a mixture of (Z)- and (E)- (1:1)
also borylative cyclized and heterocycle compounds cis-3l4and was conducted. (Z)- was consumed considerably faster than
. When the reactions were conducted separately using (Z)-
and (E)- under the same reaction conditions, similar
account for the stereoconvergent features of the reaction kinetics were observed, and no (E)-
transformation (Scheme 2). Pathway i.e., the Z-E GC analysis in the reaction using (Z)-
isomerization mechanism, involves the isomerization of (Z)-1a Information for details).
to (E)-1a prior to the addition of borylcopper (LCu-Bpin) to its The results obtained from these experiments indicate that
double bond. (E)-1a then undergoes a syn-addition with addition of the borylcopper catalytic species to the C–C double
borylcopper to produce intermediate , with a subsequent bond of α,β-unsaturated esters is the rate-determining step.
In addition, the variation in substrate conversion with time
4
and (Z)-
4,
4
4
4
1
cis-3m were obtained in moderate yields (entries 12
‒
14) .
(E)-4
Two possible reaction mechanisms were then proposed to
4
4
4
was detected by
1
,
4 (see Supporting
A
intramolecular oxidative addition (to form
B
) and reductive Moreover, the addition of borylcopper to the (Z)-isomers is
elimination yielding product cis-3a. Pathway
2, i.e., the enolate faster than its addition to the (E)-isomers and also than the Z-E
mechanism, initially involves the adducts formed from the isomerization process. These kinetic studies therefore indicate
addition of (Z)-1a/(E)-1a with borylcopper undergoing a fast that Pathway 2 is a more plausible mechanism, as it accounts
enolation process to form species
enolate oxygen atom and the boron atom of species
C
. Upon coordination of the for the stereoconvergent characteristics and excellent syn-
, a five- selectivity of the reaction. As such, trans-3a is likely produced
C
membered ring is formed. However, for catalysts bearing bulky through a transition state, in which no O‒B interaction exists,
ligands (e.g., dppf, binap, PCy , or IPr), interactions between due to interactions between the bulky ligand and the Bpin
3
the ligand and the boron group likely prevent the formation of group.
such a five-membered ring. Subsequently, species
an intramolecular nucleophilic substitution reaction via stereoconvergent borylative cyclization of ω-methylate-
transition state , in which the ester group and the boron functionalized α,β-unsaturated esters and ketones to yield
atom are on the same side of the forming ring. This results in five- and six-membered boron-substituted carbocycles and
the formation of cis-3a heterocycles with excellent cis-selectivity (cis:trans >99:1). The
C
undergoes
In summary, we successfully developed a Cu-catalyzed
D
.
We also found that the Z-E isomerization process takes enolation of adducts formed from borylcopper and α,β-
place in α,β-unsaturated esters. For example, (Z)-ethyl unsaturated esters, in addition to coordination between the
crotonate and (Z)-ethyl cinnamate isomerized to give their enolate oxygen and the boron atom, account for such
corresponding (E)-isomers at 23 °C under the reaction stereoconvergence and excellent cis-selectivity. This result is of
conditions (e.g. (Z)-ethyl cinnamate is transformed into a particular importance, as few synthetic examples of cis-
mixture of Z/E = 5/1 over 8 min at 23
conditions outlined in Table 1, entry 10).
°
C under the reaction substituted cyclic boronates have been reported previously. In
addition, we expect that our catalytic system will be widely
To differentiate between the two reaction mechanisms, we accessible, as it employs commercially available materials, and
carried out Cu-catalyzed hydroboration reactions using (E)-
the reaction is conducted under mild conditions. Further
and (Z)-
(Table 3, see Supporting Information for details). studies into additional transformations and the asymmetric
Hydroboration reactions of (E)- and (Z)-
were conducted in synthesis of the cis-products are currently underway.
4
4
4
4
Scheme 2. Two plausible mechanistic pathways for the transformation.
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Table 3. Variation of the (E)-4 and (Z)-4 conversions with time in the copper-catalyzed 8. (a) H. Ito, Y. Kosaka, K. Nonoyama, Y. Sasaki and M. Sawamura,
competitive deuteroboration of a 1:1 mixture of (E)-4 and (Z)-4.
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Kosaka, M. Sawamura and H. Ito, J. Am. Chem. Soc. , 2010, 132,
1
2
1440; (c) H. Ito, T. Toyoda and M. Sawamura, J. Am. Chem. Soc.,
010, 132, 5990.
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V. Lillo, A. Prieto, A. Bonet, M. M. Díaz-Requejo, J. Ramírez, P. J.
Pérez and E. Fernández, Organometallics, 2008, 28, 659; (c) W. J.
Fleming, H. Muller-Bunz, V. Lillo, E. Fernandez and P. J. Guiry,
Org. Biomol. Chem., 2009, 7, 2520; (d) T. Shiomi, T. Adachi, K.
Toribatake, L. Zhou and H. Nishiyama, Chem. Commun., 2009,
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75, 3458; (f) X. Feng and J. Yun, Chem. Eur. J., 2010, 16, 13609;
Time(min)
2
85
35
5
99
59
10
100
76
20
100
96
30
100
100
(
(
Z)-4
E)-4
Conv.(%)
(
2
g) J. M. O’Brien, K.-s. Lee and A. H. Hoveyda, J. Am. Chem. Soc.,
010, 132, 10630; (h) J. K. Park, H. H. Lackey, M. D. Rexford, K.
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Conflicts of interest
There are no conflicts of interest to declare.
5
1
Acknowledgements
7
Am. Chem. Soc., 2012, 134, 8277; (m) T. Iwai, Y. Akiyama and M.
Sawamura, Tetrahedron: Asymmetry, 2013, 24, 729; (n) G.
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K. Toribatake, L. Zhou, A. Tsuruta and H. Nishiyama,
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C.-F. Wang, Y.-P. Ruan, A.-E. Wang and P.-Q. Huang,
Tetrahedron: Asymmetry, 2013, 24, 492; (q) Q. Liu, B. Tian, P.
Tian, X. Tong and G.-Q. Lin, Chin. J. Org. Chem., 2015, 35, 1.
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This work was supported by the Open Project Program of the
State Key Lab of Elemento-organic Chemistry, Nankai
University (Grant No. 201506), Natural Science Foundation of
Shaanxi Province (Grant No. 2016JM2005), and National
Natural Science Foundation of China (Grant No. 21673183).
Notes and references
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3. The direct hydroboration of cycloalkkenyl carboxylate ester
leads to a mixture of cis/trans diastereomers, see ref. 2.
4. cis-3l and cis-3m decompoesed to compecated mixtures upon
silica gel chromatography seperation. However, 1H NMR
spectra of crude products and HRMS clearly show the formation
of them.
4
5
6
7
. T. Jiang, T. Bartholomeyzik, J. Mazuela, J. Willersinn and J.-E.
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635.
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